US20040050787A1 - Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target - Google Patents

Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target Download PDF

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Publication number
US20040050787A1
US20040050787A1 US10/243,560 US24356002A US2004050787A1 US 20040050787 A1 US20040050787 A1 US 20040050787A1 US 24356002 A US24356002 A US 24356002A US 2004050787 A1 US2004050787 A1 US 2004050787A1
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sample
well
interest
molecules
membrane structure
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US10/243,560
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Elena Chernokalskaya
Phillip Clark
William Kopaciewicz
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EMD Millipore Corp
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Individual
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Priority to US10/243,560 priority Critical patent/US20040050787A1/en
Assigned to MILLIPORE CORPORATION reassignment MILLIPORE CORPORATION ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHERNOKALSKAYA, ELENA, CLARK, PHILLIP, KOPACIEWICZ, WILLIAM
Priority to JP2003279673A priority patent/JP4008862B2/ja
Priority to DE60304259T priority patent/DE60304259T2/de
Priority to ES03017402T priority patent/ES2256626T3/es
Priority to EP03017402A priority patent/EP1398614B1/fr
Publication of US20040050787A1 publication Critical patent/US20040050787A1/en
Priority to US11/483,927 priority patent/US20060263259A1/en
Abandoned legal-status Critical Current

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N1/00—Sampling; Preparing specimens for investigation
    • G01N1/28—Preparing specimens for investigation including physical details of (bio-)chemical methods covered elsewhere, e.g. G01N33/50, C12Q
    • G01N1/40—Concentrating samples
    • G01N1/405—Concentrating samples by adsorption or absorption
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/02—Burettes; Pipettes
    • B01L3/0241—Drop counters; Drop formers
    • B01L3/0262—Drop counters; Drop formers using touch-off at substrate or container
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L3/00—Containers or dishes for laboratory use, e.g. laboratory glassware; Droppers
    • B01L3/50—Containers for the purpose of retaining a material to be analysed, e.g. test tubes
    • B01L3/502—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures
    • B01L3/5025—Containers for the purpose of retaining a material to be analysed, e.g. test tubes with fluid transport, e.g. in multi-compartment structures for parallel transport of multiple samples
    • B01L3/50255—Multi-well filtration
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/02—Details
    • H01J49/04—Arrangements for introducing or extracting samples to be analysed, e.g. vacuum locks; Arrangements for external adjustment of electron- or ion-optical components
    • H01J49/0409—Sample holders or containers
    • H01J49/0418—Sample holders or containers for laser desorption, e.g. matrix-assisted laser desorption/ionisation [MALDI] plates or surface enhanced laser desorption/ionisation [SELDI] plates
    • H—ELECTRICITY
    • H01—ELECTRIC ELEMENTS
    • H01J—ELECTRIC DISCHARGE TUBES OR DISCHARGE LAMPS
    • H01J49/00—Particle spectrometers or separator tubes
    • H01J49/26—Mass spectrometers or separator tubes
    • H01J49/34—Dynamic spectrometers
    • H01J49/40—Time-of-flight spectrometers
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2200/00—Solutions for specific problems relating to chemical or physical laboratory apparatus
    • B01L2200/06—Fluid handling related problems
    • B01L2200/0631—Purification arrangements, e.g. solid phase extraction [SPE]
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
    • B01L—CHEMICAL OR PHYSICAL LABORATORY APPARATUS FOR GENERAL USE
    • B01L2300/00—Additional constructional details
    • B01L2300/08—Geometry, shape and general structure
    • B01L2300/0809—Geometry, shape and general structure rectangular shaped
    • B01L2300/0829—Multi-well plates; Microtitration plates
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/25375—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.]
    • Y10T436/255—Liberation or purification of sample or separation of material from a sample [e.g., filtering, centrifuging, etc.] including use of a solid sorbent, semipermeable membrane, or liquid extraction
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
    • Y10T436/00—Chemistry: analytical and immunological testing
    • Y10T436/25—Chemistry: analytical and immunological testing including sample preparation
    • Y10T436/2575—Volumetric liquid transfer

Definitions

  • Matrix-assisted laser desorption/ionization (MALDI) analysis is a useful tool for solving structural problems in biochemistry, immunology, genetics and biology.
  • Samples are ionized and a time of flight (TOF) analyzer is used to measure ion masses.
  • TOF analysis begins when ions are formed and are accelerated to a constant kinetic energy as they enter a drift region. They arrive at a detector following flight times that are proportional to the square root of their masses. A mass spectrum is created because ions of different mass arrive at the detector at different times.
  • Mass spectrometry can be a particularly powerful tool in the fields of drug discovery and development, genotyping, and proteome research.
  • Current trends in research are to analyze larger and larger numbers of samples using automated handling equipment or robotics. Quantities of individual samples are from the nano-mole levels to atto-mole levels. As a result, instrumentation is becoming more sensitive and a need exists for sample handling formats to be miniaturized, high density and disposable.
  • Sample preparation prior to analysis often involves desalting and concentration of samples (e.g., peptides) down to a 1-2 microliter volume. These volumes are likely to decrease to nanoliter volumes in time. Simultaneous preparation and analysis of multiple samples is often desirable.
  • Multiwell plates have been developed for simultaneous assay, typically consisting of 96, 384 or 1536 reaction vessels or wells per plate.
  • sample preparation devices such as the ZipTip® device commercially available from Millipore Corporation, are excellent tools for sample preparation prior to MALDI analysis. They are a single sample processor that can be used to spot sample onto the MALDI target manually or by automated equipment. More specifically, U.S. Pat. Nos. 6,048,457 and 6,200,474 teach the formation of cast membrane structures for sample preparation that are formed by phase inversion of a particle loaded polymer system at the housing orifice. The polymer is precipitated when the housing (containing the soluble polymer/particle lacquer) is immersed in a precipitation bath (typically water).
  • a precipitation bath typically water
  • the insertion creates a slight liquid pressure across the lacquer such that the water intrudes upon the polymer creating an open sponge-like structure upon precipitation.
  • a semipermiable membrane film that creates a high resistance to flow.
  • this barrier is either abraded of cut off, the resulting structure is highly permeable.
  • the resulting device is designed to allow flow under the low differential pressures generated by a common 10 microliter hand-held pipettor (e.g. Gilson, Pipetman).
  • sample is lost to due adherence to the interfaces of these devices. Since sample amounts are typically in the femotmole range, sample losses are unacceptable. Furthermore, centrifugation is also not amenable to automation, as the plate must be manually placed and removed into and from the centrifuge.
  • a key to achieving high sensitivity and strong MALDI signals is by eluting the bound peptides in as high a concentration as possible. This can be accomplished by using minimum elution volume and reducing handling steps.
  • the apparatus in accordance with an embodiment of the present invention includes a plurality of wells each in fluid communication with a respective outlet or drainage opening, optionally containing a three dimensional membrane structure preferably comprising a plurality of sorptive particles entrapped in a porous polymer matrix so as to form a device capable of carrying out solid phase extraction.
  • the apparatus is designed to allow for direct spotting onto a MALDI target, thereby eliminating a transfer step.
  • the present invention is also directed towards a method of sample preparation, deposition and analysis using the apparatus of the present invention.
  • FIG. 1 is a perspective view of a single well of a multi-well device, with the composite structure shown in expansion in Detail A;
  • FIGS. 2A, 2B, 2 C and 2 D show four steps of the elution and transfer process in accordance with the present invention
  • FIG. 3 is a graph comparing % sequence coverage in various elution techniques
  • FIG. 4A is a spectrum of a ⁇ -galactosidase sample eluted into a microtiter plate using vacuum in accordance with the prior art
  • FIG. 4B is a spectrum of a B-galactosidase sample eluted using centrifugation in accordance with the prior art
  • FIG. 4C is a spectrum of a ⁇ -galactosidase sample eluted directly onto a MALDI target in accordance with the present invention.
  • FIG. 5 is a cross-sectional view of a well positioned over a MALDI-TOF target substrate and coupled to a vacuum manifold in accordance with the present invention.
  • Suitable substrate materials for the sample preparation device of the present invention are not particularly limited, and include plastics (such as polyethylene and polypropylene), glass and metal, such as stainless steel.
  • the substrate materials should not interfere with the operation of the device or the chemicals to be used in the procedure.
  • Polyolefins, and particularly polypropylene, are preferred materials.
  • membrane as used herein includes permeable and semi-permeable three dimensional structures with or without particles, having a porosity suitable for the desired application.
  • composite structure as used herein includes filled membranes.
  • FIG. 1 there is shown a single well 12 of a sample preparation device that has a plurality of wells, such as 384.
  • a well 12 is defined by a vertically extending fluid impervious side wall 14 and a sloping bottom portion 13 .
  • the middle and upper portions of the well 12 preferably have a uniform diameter and are substantially cylindrical in cross-section, although other configurations are contemplated and within the scope of the present invention.
  • the lower portion of the well 12 preferably tapers downwardly, in the direction of fluid flow, towards a bottom portion 13 , which slopes inwardly towards a center, thereby having a frusto-conical configuration.
  • Bottom portion 13 has a spout 15 that is preferably centrally located in the well.
  • the spout 15 is a bore, preferably cylindrical and axially aligned with the central longitudinal axis of the well 12 .
  • the dimensions of the bore determine the dimensions of the membrane structure contained therein, which determine, in part, the characteristics of the droplets that form upon flow through the membrane structure.
  • Suitable bore diameters include from about 0.2 to about 2 mm, more preferably from about 0.4 to about 0.8 mm, with a diameter of 0.5 mm being preferred.
  • Suitable bore heights include from about 0.2 to about 2 mm, with 1 mm being preferred.
  • At least a portion of the spout 15 preferably includes an adsorptive membrane structure 25 .
  • Suitable adsorptive membrane structures are cast-in-place polymer bound, particle laden adsorptive membrane structures, such as those comprised of chromatographic beads which have been adhered together with a binder and disclosed in U.S. Pat. Nos. 6,048,457 and 6,200,474, the disclosures of which are hereby incorporated by reference.
  • One such preferred structure is a three-dimensional structure comprising a plurality of sorptive particles entrapped in a porous polymer matrix and having an aspect ratio (average diameter to average thickness) of less than about 10, preferably less than about 5.
  • the structure 25 may be coterminous with the bottom of the spout 15 , and extends into the body of the spout 15 , preferably extending through substantially the entire depth of the spout 15 .
  • Devices in accordance with the present invention may incorporate a plurality of membrane structures having resin materials with different functional groups to fractionate analytes that vary by charge, size, affinity and/or hydrophobicity; alternately, a plurality of devices containing different individual functional membranes may be used in combination to achieve a similar result.
  • one or more membranes can be cast in a suitable housing and functionality can be added before or after casting.
  • the membrane structure 25 is located at the distal end of the drain 15 , and has a volume of about 300 nanoliters.
  • the drain preferably has a small internal diameter, such as about 0.5 millimeters, so that the membrane structure is relatively small and therefore requires less elution volume.
  • sample dilution is minimized due to the reduction or absence of deadspace.
  • the spout 15 In order to minimize elution volume and deposit the sample (i.e., “spot”) efficiently on the target substrate, the spout 15 must be kept in close proximity to the target.
  • a molded stand-off collar or skirt 30 partially or completely circumscribing each spout 15 is formed in the device to support the device on the substrate and maintain a suitable gap or distance “x” between the outlet of the spout 15 and the target surface 50 .
  • this gap is smaller than the diameter of the liquid drop 51 that forms as the eluant transfers from the membrane structure 25 to the target surface 50 .
  • a suitable gap “x” for a 1 microliter elution is about 0.15 to about 0.020 inches (about 0.5 mm), with a maximum gap of about 0.035 inches.
  • a suitable gap for a 2 microliter elution is from about 0.020 to about 0.030 inches, with a maximum of about 0.05 inches.
  • Gaps exceeding the maximum do not allow for the effective transfer of eluant in a minimum (or a reasonable amount) of volume. If the gap is too small, the transfer will occur, but the spots tend to be large and irregular because the drop does not fully transfer; it fills the gap and can bubble if air flows through the structure.
  • the minimum gap is such that an elution droplet formed contacts the target surface 50 and releases from the spout outlet leaving a gap, so that the elution droplet is not disrupted by air flow through the spout.
  • the collar 30 is annular and conveniently defines a volume bounded by the bottom of the well and the target surface 50 that allows vacuum to reach the spout 15 .
  • One or more vents 54 are formed in the collar 30 for this purpose.
  • posts or other structures could be used to create the gap and ensure that the spout can receive negative pressure.
  • Suitable substrates or targets are those conventionally used in MALDI TOF mass spectrometry. They are substantially planar, conductive, and are dimensioned to fit in ionization chambers of the MALDI instrument. Metallics such as stainless steel are typical.
  • the present invention utilizes the evaporation problem discussed above as a processing solution, and eliminates a transfer step previously necessary when using conventional methods.
  • sample is introduced into one or more wells of the multi-well plate by any suitable means, such as by pipetting.
  • the molecules of interest are captured by the membrane structure 25 present in each well.
  • a wash step is optionally carried out.
  • the plate is positioned on a vacuum manifold 60 (sealed with sealing gasket 61 ) and over a planar MALDI target substrate, for example, appropriately positioned below the spout outlet.
  • vacuum preferably about 5 inches Hg
  • an elution solvent about 1-2 microliters
  • a suitable elution solvent such as an acetonitrile/matrix mixture, preferably a 50% acetonitrile/0.1% TFA mixture can be used, and vacuum is applied.
  • the elution volume exits the spout 15 and contacts the target positioned beneath the spout and rapidly evaporates on the target, leaving the sample crystals ready for analysis in a convenient array (corresponding to the array of wells 12 ) such as by MALDI. Since a transfer step is eliminated, losses are minimized and sample processing Fime is reduced. Crystal formation is excellent, and MALDI signal sensitivity is enhanced.
  • One method of identifying an unknown protein is to digest it with ca. bovine trypsin generating a unique set of peptides.
  • the collective masses of these peptides as determined by mass spectrometry represent a fingerprint that can be searched against a database.
  • the quality of the database match can be assessed by several complex-scoring systems.
  • one simple means of scoring is the amount of protein sequence that can be identified by the mass spectrum. This parameter is typically referred to in the field as % sequence coverage or % coverage. In most cases, with a high performance MALDI TOF MS system that is accurate to 50 ppm of a mass unit, it is possible to identify a protein with as little as ca. 12% of its sequence.
  • FIG. 3 shows the sequence coverage obtained from ⁇ -galactosidase ( E. coli ) samples (50, 100 and 200 fmol) that were digested with bovine trypsin, transferred to a MALDI TOF MS target by 3 different means and analyzed.
  • ⁇ -galactosidase E. coli
  • MALDI TOF MS target 3 different means and analyzed.
  • the sample was desorbed from the plate in 15 microliters of volume (50% acetonitrile containing MALDI matrix, e.g. ⁇ -cyano-4-hydroxy-cinnamic acid) using a vacuum manifold (at 5 inches Hg) into a 96-well “V” bottom polypropylene microtiter plate.
  • FIG. 4A is the spectra obtained when the membrane was eluted into a microtiter plate well with 15 microliters of 50% acetonitrile containing MALDI Matrix using vacuum (5 inches Hg) and then spotted (2 microliters) onto a MALDI TOF MS target.
  • FIG. 4B was obtained by eluting the membrane with 2 microliters of 50% acetonitrile containing MALDI Matrix using centrifugation (15 seconds @ 1500 ⁇ g) and then spotted (2 microliters).
  • FIG. 4A is the spectra obtained when the membrane was eluted into a microtiter plate well with 15 microliters of 50% acetonitrile containing MALDI Matrix using vacuum (5 inches Hg) and then spotted (2 microliters) onto a MALDI TOF MS target.
  • FIG. 4B was obtained by eluting the membrane with 2 microliters of 50% acetonitrile containing MALDI Matrix using centrifugation (15 seconds @ 1500
  • FIG. 4C is a spectrum of a well that was eluted/spotted (2 microliters) by vacuum (5 inches Hg) directly onto the MALDI TOF MS target in accordance with the present invention.
  • FIG. 4C shows coverage of 23%, compared to 20% using centrifugation and virtually no coverage with indirect vacuum.

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US10/243,560 2002-09-13 2002-09-13 Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target Abandoned US20040050787A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
US10/243,560 US20040050787A1 (en) 2002-09-13 2002-09-13 Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target
JP2003279673A JP4008862B2 (ja) 2002-09-13 2003-07-25 試料調製およびｍａｌｄｉ−ｔｏｆターゲット上への溶離剤の直接スポッティングのための器械および方法
DE60304259T DE60304259T2 (de) 2002-09-13 2003-07-31 Vorrichtung und Verfahren zur Probenvorbereitung und Direkt spotting von Eluenten auf einen Maldi-Tof-Ziel
ES03017402T ES2256626T3 (es) 2002-09-13 2003-07-31 Aparato y metodo para la preparacion de muestras y manchado directo de eluentes sobre una diana de maldi-tof.
EP03017402A EP1398614B1 (fr) 2002-09-13 2003-07-31 Appareil et méthode pour la preparation d'echantillons et le spotting direct d'éluant sur cibles maldi-tof
US11/483,927 US20060263259A1 (en) 2002-09-13 2006-07-10 Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target

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US10/243,560 US20040050787A1 (en) 2002-09-13 2002-09-13 Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target

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US11/483,927 Abandoned US20060263259A1 (en) 2002-09-13 2006-07-10 Apparatus and method for sample preparation and direct spotting eluants onto a MALDI-TOF target

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JP (1) JP4008862B2 (fr)
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US10335785B2 (en) 2010-12-17 2019-07-02 Biomerieux, Inc. Methods for the isolation, accumulation, characterization and/or identification of microorganisms using a filtration and sample transfer device

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EP2128593B1 (fr) * 2007-07-20 2013-01-09 ARKRAY, Inc. Dispositif d'alimentation d'échantillon et dispositif d'analyse d'échantillon l'utilisant
WO2014187655A1 (fr) * 2013-05-21 2014-11-27 Thermo Electron Manufacturing Limited Dispositif et procédé permettant de séparer les composants d'une solution
CN103543059A (zh) * 2013-10-17 2014-01-29 常熟市梅李镇香园稻米专业合作社 一种提取稻米中无机砷的方法

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EP1398614B1 (fr) 2006-03-29
ES2256626T3 (es) 2006-07-16
US20060263259A1 (en) 2006-11-23
DE60304259T2 (de) 2006-12-28
EP1398614A3 (fr) 2004-06-23
DE60304259D1 (de) 2006-05-18
JP2004264278A (ja) 2004-09-24
EP1398614A2 (fr) 2004-03-17
JP4008862B2 (ja) 2007-11-14

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